Histone deacetylases (HDACs) have been used as pharmacological targets for the treatment of various diseases. Some non-selective HDAC inhibitors (HDACi) have been clinically-used as therapeutic agents for treatment of hematological cancers but their cytotoxic side effects are an important downside. The discovery of more selective inhibitors has certified the involvement of individual HDACs in pathological processes but the elucidation of the role of specific family members in inflammatory responses still remains a challenge. Here, we report the development of closely related, structural analogues of the clinically-used HDACi Entinostat via a chemical epigenetic approach. Three compounds were designed and synthesized in which the cap moiety of Entinostat was replaced by an azobenzene group that is either para, meta or ortho substituted. The compounds were then evaluated for selectivity towards HDACs 1–3 and their effect on pro-inflammatory gene expression in macrophages. One analogue, compound 4, lacked selectivity and demonstrated inhibition of NF-κB reporter gene activity and pro-inflammatory gene expression in RAW264.7 macrophages, thus indicating that there is a delicate balance between the selectivity of HDACi over specific family members and their pro- or anti-inflammatory effects.